Conventional sampling methods for collecting body fluids typically involve invasion of the organism (e.g., physical disruption of the skin). Such invasive processes are both painful and messy. The difficulty and pain involved with the process provides a disincentive to the patient to perform the procedure.
Several techniques have been reported that involve little or minimal invasion of the skin. Exemplary such techniques are sonophoresis, iontophoresis and vacuum.
The use of iontophoresis requires using electrodes containing oxidation-reduction species as well as passing electric current through the skin. Iontophoresis has also been used to increase skin permeability. Despite the effective use of iontophoresis for skin permeation enhancement, there are problems with irreversible skin damage induced by the transmembrane passage of current.
Vacuum has been reported to draw fluid transcutaneously while avoiding the complications of invasive procedures. The use of vacuum to extract fluid across the skin is limited because of the relative impermeability of the stratum corneum.
The art discloses methods of using ultrasound traveling waves to enhance the rate of permeation of a drug medium into a selected area of contact of an individual or to enhance the rate of diffusion of a substance through the area of contact of an individual. The use of ultrasound traveling waves may induce localized skin heating.
Thus, there continues to be a need to provide a process and apparatus for sampling extracellular fluid across the skin of an animal.
The present disclosure provides ultrasonic standing waves to enhance permeation and mass transport through skin. While prior art techniques use ultrasonic traveling waves to enhance permeation of the skin, traveling waves do not enhance mass transport of the interstitial fluids. Standing waves on the other hand may promote permeation as well as mass transport. High velocity gradients exhibited by a standing wave sound field can provide enhanced mass transport specifically at boundary layer and at air-fluid interfaces within the structures of skin.
Furthermore, standing waves differ from traveling waves in radiation force. As understood in the art, radiation force is the time-average force exerted on a rigid spherical object immersed in a sound field over a number of cycles. In other words, the radiation force of a traveling wave is the gradient of the kinetic energy density minus the gradient of the potential density plus a phase factor. In contrast, the sum of the kinetic and potential energy density of a standing wave is independent of distance, and so their gradients are equal in magnitude but opposite in sign. The phase factor equals zero since it is constant with distance. Thus, the force for the standing wave is a constant times the gradient of the potential energy density whose maximum is equal to twice the potential energy density.
For example, in a traveling wave of pressure amplitude A, a particle is acted on by a small steady state force in the direction of the wave. If the wave is uniform, then the force is the same independent of the particle's position. However, in a standing wave the total pressure amplitude varies in space or position. The maximum amplitude is 2A and occurs in planes spaced at a half-wavelengths apart. The radiation force on the particle varies in both magnitude and direction. The force reverses direction every quarter wavelength.
The ratio of the maximum standing wave radiation force to the traveling wave value is approximately (1/kR).sup.3, where R is the particle radius and k is 6.28 divided by the wavelength. The wavelength in soft tissue is about 1.5/f millimeters, where f is the frequency in MHz (e.g. at 1 MHz the wavelength is 1.5 millimeters). If the radius of a particle is 0.01 mm and the wavelength is 1.5 mm, one obtains 0.042 for kR, 0.000073 for (kR).sup.3, and 13,600 for (1/kR).sup.3. As is apparent, the radiation force produced by a standing wave relative to a traveling wave is significant. While the radiation force is calculated for rigid spherical particles, the relationship is applicable to small biological particles such as blood cells, intracellular bodies such as chloroplasts, and mitochondria, as these cells and organelles exist in vivo, since these structures in which they are located are comparable to a suspending medium. Thus, the radiation force is applicable to biological structures existing within animal skin.
There are several advantages to the use of standing waves in enhancing skin permeability and mass transport for diagnostic sampling. First, the energy required for diagnostic sampling is less than that required for traveling wave techniques. This is evident with the fact that the radiation force generated by a standing wave is larger in comparison to a traveling wave of the same energy. Second, a standing wave using significantly less intensity but effectively producing the necessary permeability and, in addition mass transport effects, would alleviate the danger of bioacoustic effects. In addition, acoustic sources of low energy typically require less electrical power and are more amenable to miniaturization. Finally, the acoustic effect of standing waves can be localized within the stratum corneum, which is the rate-limiting barrier to transport in skin, while low frequency traveling waves tend to penetrate deeply into skin significantly beyond the stratum corneum. This can potentially cause undesirable bioeffects at bone-tissue interfaces that produce discomfort to a subject undergoing treatment, e.g., drug delivery or extracellular-fluid-extraction for diagnostic purposes.
The present disclosure provides, in part, a surface-acoustic-wave (SAW) device to generate standing waves within the stratum corneum region as a means for enhancing permeability and mass transport of analytes across the skin. A SAW device provides safe-coupling of sound field adjacent to skin since the electrodes needed to excite the waves are mounted on the opposite side of the acoustic device away from skin.